Alzheimer's disease (AD) is a neurodegenerative disease characterized by a deterioration of cognitive skills, eventually progressing to dementia. AD pathology is believed to result from an accumulation of insoluble amyloid plaques and neurofibrillary tangles. Recent studies have demonstrated a role for two highly related protein kinases, glycogen synthase kinase-31 and 2 (GSK-31 and GSK-32), in the regulation of 2-amyloid peptide production. These molecules have previously been directly implicated in neurofibrillary tangle formation, suggesting that GSK-3 isoforms are important mediators of AD pathology. Our long-term goal is to better understand how GSK-3 activity contributes to the pathogenesis of AD. As a step toward attaining this long-term goal, we have created mice that will allow for the conditional knockout of both GSK-31 and GSK-32. The specific hypothesis we wish to test is that inactivation of GSK-31 decreases 2-amyloid peptide production and prevents the onset of AD pathology. These mice, and the cells derived from these mice, will permit us to begin addressing the molecular basis of how GSK-3 activity contributes to AD pathogenesis and neurodegeneration. Specific Aim 1: Define the contribution of each GSK-3 isoform toward the events leading to the pathogenesis of Alzheimer's disease. Specific Aim 2: Delineate the molecular basis of the differential effects of GSK-31 and GSK-32 on the production of 2-amyloid peptides. Specific Aim 3: Examine the effects of conditionally deleting GSK-31 and GSK-32 on the pathogenesis of Alzheimer's disease. The aims proposed above utilize our novel GSK-3 conditional knockout mice, thus affording us an opportunity to make significant strides toward understanding the molecular mechanism by which GSK-3 isoforms participate in Alzheimer's disease. PUBLIC HEALTH RELEVANCE: This application proposes experiments designed to gain a better understanding of how Alzheimer's disease develops. It is our hope that this increased knowledge will lead to the development of therapeutics capable of slowing or preventing the symptoms associated with Alzheimer's disease. [unreadable] [unreadable]